For over 25 years, evidence has accumulated indicating that selenium is effective in reducing cancer incidence in animal model systems. Both epidemiological data and the results of selenium supplementation trials have suggested that selenium may be effective in humans as well. The mechanism of selenium-mediated chemoprevention remains unknown. Recent genetic data, as well as preliminary results included in this application, have implicated the selenium-dependent, antioxidant enzyme glutathione peroxidase (GPx) in cancer risk and perhaps the mechanism of chemoprevention by selenium. The broad objective of this proposal is to evaluate a role for GPx in cancer etiology and risk. To achieve this goal, the investigators will focus on 3 specific aims. The first is to determine whether certain genetic GPx variants or LOH at that genetic locus is associated with certain types of malignancies. This will be accomplished by analyzing DNA obtained from both tumors and cancer- free individuals to determine variant allele frequencies. The second specific aim will be to determine whether a variant form of GPx, containing a leucine instead of a proline at codon 198, is associated with altered GPx activity. The third specific aim will be to determine whether levels of GPx activity can influence mutation frequencies using a shuttle vector system and human tissue culture cells engineered to overexpress that enzyme. Collectively, these studies will elucidate an association of certain GPx alleles with cancel risk and the protection offered by selenium, and provide new mechanistic information as to how GPx levels may contribute to cancer incidence. These studies may result in the identification of individuals who are at risk of cancer as well as those that may benefit from selenium supplementation.